title: Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy.
abstract: Preclinical studies and initial clinical trials have documented the feasibility of adenoassociated virus (AAV)-mediated gene therapy for hemophilia B. In an 8-year study, inhibitor-prone hemophilia B dogs (n = 2) treated with liver-directed AAV2 factor IX (FIX) gene therapy did not have a single bleed requiring FIX replacement, whereas dogs undergoing muscle-directed gene therapy (n = 3) had a bleed frequency similar to untreated FIX-deficient dogs. Coagulation tests (whole blood clotting time [WBCT], activated clotting time [ACT], and activated partial thromboplastin time [aPTT]) have remained at the upper limits of the normal ranges in the 2 dogs that received liver-directed gene therapy. The FIX activity has remained stable between 4% and 10% in both liver-treated dogs, but is undetectable in the dogs undergoing muscle-directed gene transfer. Integration site analysis by linear amplification-mediated polymerase chain reaction (LAM-PCR) suggested the vector sequences have persisted predominantly in extrachromosomal form. Complete blood count (CBC), serum chemistries, bile acid profile, hepatic magnetic resonance imaging (MRI) and computed tomography (CT) scans, and liver biopsy were normal with no evidence for tumor formation. AAV-mediated liver-directed gene therapy corrected the hemophilia phenotype without toxicity or inhibitor development in the inhibitor-prone null mutation dogs for more than 8 years.
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, AL, USA.
authors.forename: Glenn P
authors.initials: GP
authors.lastname: Niemeyer
authors.forename: Roland W
authors.initials: RW
authors.lastname: Herzog
authors.forename: Jane
authors.initials: J
authors.lastname: Mount
authors.forename: Valder R
authors.initials: VR
authors.lastname: Arruda
authors.forename: D Michael
authors.initials: DM
authors.lastname: Tillson
authors.forename: John
authors.initials: J
authors.lastname: Hathcock
authors.forename: Frederik W
authors.initials: FW
authors.lastname: van Ginkel
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
authors.forename: Clinton D
authors.initials: CD
authors.lastname: Lothrop
mesh_terms: D000818:Animals; D004279:DNA, Viral / Q000235:genetics; D000229:Dependovirus / Q000235:genetics*; D004285:Dogs; D005164:Factor IX / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors / Q000235:genetics; D002836:Hemophilia B / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D007108:Immune Tolerance / Q000276:immunology; D008099:Liver / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D013997:Time Factors; D014057:Tomography, X-Ray Computed
chemical_list: D004279:DNA, Viral; D012333:RNA, Messenger; D005164:Factor IX